WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer

FA Poujade, A Mannion, N Brittain, A Theodosi, E Beeby, KB Leszczynska, EM Hammond, John Greenman, C Cawthorne, IM Pires

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Metastatic spread is responsible for the majority of cancer-associated deaths. The tumour microenvironment, including hypoxia, is a major driver of metastasis. The aim of this study was to investigate the role of the E3 ligase WSB-1 in breast cancer biology in the context of the hypoxic tumour microenvironment, particularly regarding metastatic spread.

Methods: In this study, WSB-1 expression was evaluated in breast cancer cell lines and patient samples. In silico analyses were used to determine the impact of WSB-1 expression on distant metastasis-free survival (DMFS) in patients, and correlation between WSB1 expression and hypoxia gene expression signatures. The role of WSB-1 on metastasis promotion was evaluated in vitro and in vivo.

Results: High WSB1 expression was associated with decreased DMFS in ER-breast cancer and PR-breast cancer patients. Surprisingly, WSB1 expression was not positively correlated with known hypoxic gene expression signatures in patient samples. Our study is the first to show that WSB-1 knockdown led to decreased metastatic potential in breast cancer hormone receptor-negative models in vitro and in vivo. WSB-1 knockdown was associated with decreased metalloproteinase (MMP) activity, vascular endothelial growth factor (VEGF) secretion, and angiogenic potential.

Conclusions: Our data suggests that WSB-1 may be an important regulator of aggressive metastatic disease in hormone receptor-negative breast cancer. WSB-1 could therefore represent a novel regulator and therapeutic target for secondary breast cancer in these patients.
Original languageEnglish
Pages (from-to)1229–1237
Number of pages9
JournalBritish Journal of Cancer
Volume118
Early online date15 Mar 2018
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • breast cancer
  • oncology

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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